Persistent infection of adult mink with the Aleutian mink disease parvovirus (ADV)leads to disturbances of immune regulation, including hypergammaglobulinemia, plasmacytosis, immune complex disease, interstitial and glomerulonephritis. Virus is neutralized in vitro, but not in vivo, and infectious immune complexes occur. Capsid based vaccines are uniformly ineffective and induce acclerated disease. Infection at the cellular level is noncytopathic and restricted. In contrast, infections in cell culture and in newborn mink are cytopathic and fully permissive. Studies in cell culture indicate that ADV induces programmed cell death (apoptosis) and is in fact dependent upon apoptosis for complete viral replication. Following infection, the major nonstructural protein, NS1, is cleaved by caspases, although not all the NS1 molecules are cut. The C-terminal cleavage product specifically translocates to the nucleus and also ?taxis? full-length NS1 into the nucleus. Direct binding between the cleaved and full-length NS1 can be demonstrated. Since NS1 must be present in the nucleus to fulfill its obligatory roles in virus replication, these findings explain the mechanism by which caspase action controls ADV replication. Suppression of the cleavage restricts ADV replication and may promote persistence. Other aims are to correlate specific genomic sequences to functional correlates, such as determinants of host-range, persistence and pathogenicity; and to study the actual structure of the ADV virion. Understanding of the structure at high resolution will enable us to (a) relate epitopes and pathogenicity determinants to discreet coordinates on the viral particle, (b) relate structural features to the unique biology of ADV in vivo. By studying chimeric and site-directed mutant ADVs, we found that control of in vivo host range and persistent infections can be separated from expression of pathogenicity, although all are governed by amino acids in the capsid. As few as 3 amino acid residues in the capsid gene control pathogenicity.